| Project/Area Number |
14207100
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | National Institute for Environmental Studies |
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Principal Investigator |
AOKI Yasunobu National Institute for Environmental Studies, Research Center for Environmental Risk, Section Chief, 化学物質環境リスク研究センター, 室長 (20159297)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Michi National Institute for Environmental Studies, Research Center for Environmental Risk, Senior Scientist, 化学物質環境リスク研究センター, 主任研究員 (60132867)
YAMAMOTO Masayuki Tsukuba University, TARA Center, Professor, 基礎医学系, 教授 (50166823)
NOHMI Takehiko National Institute of Health Sciences, Division Genetics Mutagenesis, Section Chief, 変異遺伝部, 室長 (30150890)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥50,050,000 (Direct Cost: ¥38,500,000、Indirect Cost: ¥11,550,000)
Fiscal Year 2004: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2003: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2002: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
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| Keywords | mutagen / gpt delta mouse / diesel exhaust / Nrf2 / benzo[a]pyrene / nitropyrene / transgenic mouse / in vivo mutagenesis / 変異原物質検出 / Nrf2ノックアウトマウス / benzo[a]pyrene / 変異物質検出 / 1,6-ジニトロピレン / Benzo(a)pyrene |
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| Research Abstract |
A transcription factor, Nrf2, is essential for expression of phase II enzymes and antioxidant enzymes, and contributes to a protection system against xenobiotics. We intended to reveal how mutant frequency is increased under Nrf2-deficient condition. We used gpt delta mice as a model animal for determining characteristics of in vivo mutagenesis caused by environmental mutagens. Intratracheal instillation of mutagens such as benzo[a]pyrene (B[a]P) and 1,6-dinitropyrene(1,6-DNP) caused to increase the mutant frequency linearly depending of the dose, and in vivo mutagenic potency of 1,6-DNA was shown to be higher than that of B[a]P. A predominant base substitution caused by B[a]P and 1,6-DNP was G>T and G>A, respectively, and positions of mutation hotspots on gpt gene was different between these compounds. Exposure of diesel exhaust for 12 weeks at the concentration of 3 mg/m^3 resulted to elevate the mutant frequency depending on duration of exposure. As a result of intratracheal instillation, mutagenicity of diesel exhaust particles (DEP) was shown to be derived from the extract of DEP. A predominant base substitution induced by exposure of diesel exhaust, as well as administration of DEP, was G>A, and the positions of mutation hotspots were identical to those of 1,6-DNP, suggesting that major mutagens in diesel exhaust are nitropyrenes and related compounds. We produced Nrf2-deficient gpt delta mice, and B[a]P was administered to lungs of the Nrf2(+/-) and Nrf2(-/-) mice. The mutant frequency in B[a]P-treated Nrf2(-/-) mice became twice compared to Nrf2(+/-) mice.
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